(1) Field of the Invention
The present invention relates to a pharmaceutical, in particular, a novel phenylacetamide derivative which is useful as an agent for treating diabetes.
(2) Description of Related Art
GK (glucokinase (ATP:D-hexose 6-phosphotransferase, EC2.7.1.1)) is an enzyme which is expressed in the pancreas and the liver and phosphorylates hexose, and its presence in the brain has also been revealed in recent years. This enzyme belongs to the hexokinase family and is also called an alias hexokinase IV. In comparison with other hexokinases, GK has characteristics such as 1) it has low affinity for glucose as its substrate and shows a Km value close to the blood glucose concentration, 2) it is not inhibited by glucose 6-phosphate which is its enzyme reaction product, 3) it has about half molecular weight of 50 kDa, and the like.
The human glucokinase gene is positioned at the 7th chromosome 7p13 as a single gene and controlled by 30 kb or more distant tissue-specific different promoters in pancreatic β cells and hepatic cells and uses a different first exon but the other exons 2 to 10 are common. Accordingly, in the pancreatic and hepatic GK proteins, only the N-terminal 15 residues are different.
Accompanied by the increase of blood glucose level, glucose concentration in the pancreatic β cells quickly reaches its equilibrium via a glucose transporting carrier GLUT 2, and GK detects a change in the intracellular glucose concentration and activates the glycolytic pathway. As a result of this, ATP/ADP ratio in the pancreatic β cells increases and the KATP channel is closed, and a voltage-dependent Ca channel detects this and the intracellular calcium concentration is thereby increased and release of insulin occurs. That is, GK acts as a glucose sensor in the pancreatic β cells and carries an important role in the control of insulin secretion. GK also acts as a glucose sensor in the liver, responds to the increase of blood glucose level and converts glucose into glucose 6-phosphate. As a result of this, production of glycogen increases, and the glycolytic pathway is also activated and the gluconeogenesis in the liver is thereby inhibited.
In patients whose glucose phosphorylation ability was reduced due to gene mutation of GK, hyperglycemia occurs frequently and juvenile diabetes is generated (MODY 2). On the other hand, in patients who show a low value of the Km value of GK activity due to a gene mutation, hypoglycemia is recognized after meal and at the time of fasting. That is, GK acts as a glucose sensor in human too and thereby plays an important role in maintaining normal blood glucose level. From these facts, it is expected that an agent capable of activating GK becomes an excellent therapeutic agent for type II diabetes, which corrects hyperglycemia after meal by accelerating glucose-dependent insulin secretion from the pancreatic β cells and, at the same time, inhibits release of glucose from the liver. Further, there also is a possibility that excess acceleration of insulin secretion does not occur due to acceleration of glucose uptake into the liver under hyperglycemic state after meal and therefore that the pancreatic secondary failure as a conventional problem with sulfonylurea (SU) agents can be avoided. In addition, it has been reported in recent years that apoptosis is induced when a mouse cultured pancreatic cell (MIN6N8) is cultured under high glucose. In addition, since apoptosis of the MIN6N8 cell was inhibited when glucokinase was over-expressed in this cell (Diabetes 54:2) 2602-2611 (2005), it is expected that a GK activating agent shows a pancreas protective action.
The GK which exists in the brain is a pancreas type and frequently expressed in the nerve of feeding center VMH (Ventromedial hypothalamus). Glucose-sensitive nerves are classified into a glucose excitatory GE (Glucose Excited)-neuron and a glucose suppressive GI (Glucose Inhibited)-neuron. The presence of mRNA and protein of GK is found in about 70% of the GE-neuron and about 40% of the GI-neuron.
In these glucose-sensitive nerves, GK detects increase of the intracellular glucose and activates the glycolytic pathway, and the intracellular ATP/ADP ratio thereby increases. As a result of this, the KATP channel is closed in the GE-neuron, frequency of action potential of the neuron is increased and a neurotransmitter is released. On the other hand, it is considered that a Cl− channel is concerned in the GI-neuron. In a rat in which expression of GK mRNA is increased in the VMH, compensatory action for the glucose-deficient state is reduced.
Receptors for leptin and insulin concerning in the feeding behavior are also present in the glucose-sensitive nerves. In the GE-neuron under a high glucose condition, leptin and insulin open the KATP channel and reduce the frequency of action potential. In addition, the NPY (Neuropeptide Y)-neuron which functions for the appetite promotion at ARC (arcuate nucleus) is suppressive for glucose and the POMC (Proopiomelanocortin)-neuron which functions for the appetite suppression is excitatory for glucose (Diabetes 53:2521-2528 (2004)). From these facts, it is expected that feeding behavior is suppressed by activating GK of the central, which is effective for the treatment of obesity and metabolic syndrome.
A number of compounds having the GK activation action have been reported and the compounds whose clinical efficacy has been confirmed have been already reported. However, a novel GK activator having a excellent profile regarding reduction in various side effects (actions for hERG and CYP) and solubility is still in great demand.
Phenylacetamide derivatives having a GK activation action have been reported in Patent References 1 to 25. However, there is no disclosure of cycloalkyl as a substituent which corresponds to R2 of the compound of the present invention.
Phenylacetamide derivatives having a GK activation action have been reported in Patent References 26 to 28. However, there is no specific disclosure of the compound of the present invention.
Phenylacetamide derivatives having a GK activation action have been reported in Patent References 29 to 30, which have been published after the priority date of the present application. However, there is no specific disclosure of the compound of the present invention.
Heteroaryl derivatives having a GK activation action have been reported in Patent References 31 and 32. However, the ring which corresponds to a phenyl group of the phenylacetamide of the present invention is heteroaryl. Further, there is no disclosure of cycloalkyl as a substituent which corresponds to R2 of the compound of the present invention.    [Patent Reference 1] Pamphlet of International Publication WO 00/58293    [Patent Reference 2] Pamphlet of International Publication WO 01/83465    [Patent Reference 3] Pamphlet of International Publication WO 01/85706    [Patent Reference 4] Pamphlet of International Publication WO 01/85707    [Patent Reference 5] Pamphlet of International Publication WO 02/08209    [Patent Reference 6] Pamphlet of International Publication WO 02/14312    [Patent Reference 7] Pamphlet of International Publication WO 03/95438    [Patent Reference 8] Pamphlet of International Publication WO 2006/58923    [Patent Reference 9] Pamphlet of International Publication WO 2007/026761    [Patent Reference 10] Pamphlet of International Publication WO 2005/095417    [Patent Reference 11] Pamphlet of International Publication WO 2005/095418    [Patent Reference 12] Pamphlet of International Publication WO 2006/016194    [Patent Reference 13] Pamphlet of International Publication WO 2007/051847    [Patent Reference 14] Pamphlet of International Publication WO 2004/072031    [Patent Reference 15] Pamphlet of International Publication WO 01/44216    [Patent Reference 16] Specification of U.S. Patent Application Publication No. 2001/0039344    [Patent Reference 17] Pamphlet of International Publication WO 02/46173    [Patent Reference 18] Pamphlet of International Publication WO 2004/52869    [Patent Reference 19] Pamphlet of International Publication WO 2004/063179    [Patent Reference 20] Pamphlet of International Publication WO 2005/103021    [Patent Reference 21] Pamphlet of International Publication WO 2007/007886    [Patent Reference 22] Pamphlet of International Publication WO 2007/041365    [Patent Reference 23] Pamphlet of International Publication WO 2007/041366    [Patent Reference 24] Pamphlet of International Publication WO 2007/051845    [Patent Reference 25] Pamphlet of International Publication WO 2007/051846    [Patent Reference 26] Pamphlet of International Publication WO 2004/050645    [Patent Reference 27] Pamphlet of International Publication WO 2008/05914    [Patent Reference 28] Pamphlet of International Publication WO 2008/05964    [Patent Reference 29] Specification of U.S. Patent Application Publication No. 2008/21032    [Patent Reference 30] Pamphlet of International Publication WO 2008/078674    [Patent Reference 31] Pamphlet of International Publication WO 2004/063194    [Patent Reference 32] Pamphlet of International Publication WO 2004/72066